In Western societies, the increasing prevalence of obesity has been accompanied by a dramatic increase in type 2 diabetes. Obesity is associated with an elevated inflammatory state, which is recognized as a key contributor to insulin resistance and diabetes. An important event in in this process is the recruitment and activation of macrophages to insulin-sensitive tissues. However, the mechanisms by which the diet influences systemic inflammation remain poorly understood. A key link between diet and metabolism is the microbiome of the gastrointestinal tract, producing metabolites that influence host physiology. Interestingly, the composition of commensal microbiota and associated metabolites changes dramatically in obesity. This dysbiosis has been proposed to cause a change in metabolites that interact with the host, promoting metabolic disease. Here, we aim to discover metabolite-mediated mechanisms by which microbiome-host interactions influence metabolic homeostasis to impact insulin sensitivity. Gut-produced molecules include secondary bile acids, which in addition to roles in dietary fat absorption, act as signaling molecules, activating several pathways including the farnesoid X receptor FXR to influence metabolism. In addition, N-formyl peptides are bacterial metabolic byproducts and inflammatory chemokines that activate G-protein coupled N-formyl peptide receptors (FPRs). Our preliminary data show that the N-formyl peptide fMLP stimulates macrophage chemotaxis, dependent upon the FPR1 receptor, defining a microbiome-derived chemokine/receptor system for immune cell recruitment. Furthermore, this is inhibited by primary and secondary bile acids, dependent upon FXR. Thus, bile acid stimulation of FXR leads to inhibition of fMLP/FPR1-induced macrophage activation and chemotaxis. We propose that obesity-associated dysbiosis leads to elevated pro-inflammatory N-formyl peptides and reduced anti-inflammatory bile acid activity, promoting systemic inflammation and insulin resistance through an FPR1/FXR axis. We will determine (1) mechanisms by which this metabolite-mediated axis controls macrophage activity through in vitro and in vivo macrophage migration and activity assays, and (2) the role of FPR1 in obesity-associated inflammation and insulin sensitivity through in vivo metabolic studies of FPR1 null mice. This research will elucidate metabolite-mediated mechanisms controlling inflammation and insulin sensitivity in conditions of obesity, with the ultimate goal of identifying novel targes for therapeutic treatment of insulin resistance and type 2 diabetes.
Understanding the mechanisms by which the commensal microbiota of the gastrointestinal tract interact with the host to influence metabolism, inflammation and insulin sensitivity, and how these are altered in conditions of obesity, will provide important insight into the causes of type 2 diabetes. In the future, therapeutic treatments targeting the metabolite-mediated pathways involved may be developed to improve inflammation and insulin sensitivity in obese and type 2 diabetic patients, providing better patient outcomes and reduced healthcare costs.
|McNelis, Joanne C; Lee, Yun Sok; Mayoral, Rafael et al. (2015) GPR43 Potentiates ?-Cell Function in Obesity. Diabetes 64:3203-17|